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Anthocyanins, caffeoylquinic acids, wound and ulcer healing

September 21, 2017 - 08:19 -- Pierre Lutgen

Already in 1925 burns were treated with tannins.

As it often happened in the past century the use of this natural product in the treatment of wounds was abandoned in the mid-forties due to the availability of topical antibacterial agents. It has regained interest. A clinical trial in Malawi comparing a decoction of ground tea stalks with silver sulfadiazine gave better results for bacterial growth, eschar formation.

            L Chokotho, E van Hasselt. The use of tannins in the local treatment of burn wounds-a pilot study. Malawi Med Journal, 2005, 17, 19-20

            DM Glover, A Sydow. Fifteen years of the tannic acid method of burn treatment. The American J of Surgery, 1941 51, 601-619

In Iran a polyherbal cream rich and combining decoction extracts of Malva silvestris, Solanum nigrum and Rosa damascene gave after a treatment of 14 days a healing percentage of 87.0, versus 70.8% for silver sulfadiazine. Chlorogenic acid and its parent caffeoylquinic acids also have wound healing properties, equivalent to those of silver sulfadiazine ointment.

            Chen WC, Liou SS, Liu IM, Effect of topical application of chlorogenic acid on excision wound healing in rats. Planta Med 2013 79, 616-21

An extensive study on Artemisia absinthium showed that in aqueous extracts the 4,5-o-dicaffeoylquinic acid from this plant was much more effective against gram positive bacteria like Straphylococcus aureus which infect wounds than 3,5-o-dicaffeoylquinic acid, that it inhibited the biofilm formation and potentiated commercial antibiotics.

           Fiamegos YC, Kastritis PL, Exarchou V, Han H, Bonvin AMJJ, et al. (2011) Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria. PLoS ONE 6(4): e18127. doi:10.1371/journal.pone.0018127

In our studies with the University of Louvain it was found that some varieties of Artemisia annua contained 10 times more chlorogenic acid than artemisinin.

           PM de Magalhaes, I Dupont, YJ Schneider, Anti-inflammatory effect and modulation of cytochrome P450 activities of Artemisia annua tea infusions. Food Chemistry 2012

An Italian study found a total of 1.5% dry weight of different caffeoylquinic acids in Artemisia annua.

           T Carbonara, R Pascale, P Avato, Phytochemical analysis of a herbal tea from Artemisia annua, J Pharmaceut Biomed Analysis, 2012, in press

Similar values were found in an UK study: 200 mg/L for caffeoylquinic acids in aqueous infusion versus only 50 mg/L of artemisinin. These acids also show antimalarial properties.

           JO Suberu, A Gorka, PD Roepe, AA Lapkin. Anti-Plasmodial polyvalent interactions in Artemisia annua Aqueous extract. PlosOne 2013, e80790

A recent Chinese study found 36 chlorogenic acids in Artemisia annua. Among these fifteen are monocaffeeoylquinic acids, five dicaffeoylquinic acids.

           W Zhao, W Zhang, K Dai, Identification and purification of novel chlorogenic acids in Artemisia annua. J Exp Biol aand Agric Sc. 2015. Vol 3.

A U.S. study finds a concentration of 10,94 mg/g chlorogenic acid in Artemisia annua.

           N B Daddy, PJ Weathers. Artemisia annua dried leaf tablets treated malaria resistant to ACT and i.v.artesunate: Case reports. Phytomedicine 2017

Even Artemisia vulgaris contains dicaffeoylquinic acids: 1.0 % on dry weight.

           Carnat A, Lamaison JL. Major dicaffeoylquinic acids from Artemisia vulgaris. Fitoterapia 2000, 71, 587-9.

Proanthocyanidins from other plants have similar healing effects.

           Schmidt CA, Murillo R, Merfort I. Structural and conformational analysis of proanthocyanidins from Parqapiptadenia rigida and their wound healing effects. J Nat Prod. 2011. 74, 1427-36

or from grape seeds.

           S Khanna, Sharma N, Sen CK, Dermal wound healing properties of redox-active grape seed proanthocyanidins, Free Radical Biol Med 2002 33, 1089-96

or from Artemisia plants, also on ulcers, by inhibiting Straphylococccus aureus and Streptococcus.

           JK Katadj, B Karimi, Wound healing effects of Artemisia sieberi extract on the second degree burns in mice skin. J Herbmed Pharmacol. 2016, 5, 67-71

The action of chlorogenic acids may also work via the absorption and chelation of iron which is an essential mineral for Mycobacteria.

           Hyo Ihl Chang, The function of natural pigments on gastric ulcer. 4th Internat Conf on Tissue Science and Regenerative Medicine, Rome, July 27-29 2015

           S Kumar, A Sonawane, Evaluation of antibacterial and cytotoxic activity of Artemisia nilagirica. Compl and Altern Medicine, 2014, 14:87

Caffeoylquinic acids contribute to this anti-ulcer activity. Arctium lappa is a medicinal plant known worldwide. Aqueous leave extracts are used to treat burns, ulcers, sores. It was found that the compound 1,3-o-dicaffeoylquinic acid presents gastric protection with an ED50 of 57 µg/kg which is thousand times lower than the EC50 of omeprazole at 40 mg/kg.

          J Carlotto, L da Silva, N Darora , LM de Souza, Identification of a dicaffeoylquinic acid isomer from Arctium lappa with a potent anti-ulcer activity. Talanta, 2015, 135, 50-57

Buruli ulcer is caused by a mycobacterium. A study in Nigeria showed that water extracts of Artemisia annua are effective against this infection.

          A Uba, K Ibrahim, AA Makinde, In vitro inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis by some Nigerian medicinal plants, 2003, 6, 15-19

Anthocyanins from Artemisia sieberi are efficient in healing burns. It was proposed that this effect was related to the inhibition of reactive oxygen species, the formation of complexes with poisonous materials and promotion of profilic epithelialization.

          EC Davidson. Tannic acid in the treatment of burns. Surg Gynecol Obstet. 1925 41, 202-21

Anthocyanins reduce ulcers and this is frequently the case for several Artemisia genotypes

          Yin S, Therapeutic effect of Artemisia argyi on oral ulcer in rats, Zhong Nan Da Xue Xue Bao Yi Ban, 2017

          H Sebai, MA Jabri, M Sakly, Protective effect of Artemisia campestris extract against aspirin-induced gastric lesions and oxidative stress in rats. RCS Advances, 2014, Isue 91. 

          Sun-Joong Kim, Hyo Ihl Chang. Antiulcer Activity of Anthocyanins from Rubus coreanus, J Agric and Food Chemistry, 2011, 59, 11786-93

The overexpression of metalloproteinases (MMPs), a family of zinc-dependent endopeptidases capable of degrading proteins , primarily collagen and elastin, may aggravate skin problems. The accumulated scientific evidence suggests that anthocyanins may offer protection against MMP overexpression.

          L Rojo, D Roopchand, Ilya Raskin. Role of anthocyanins in skin aging and UV-induced skin damage. CRC Press 2013, Editors: Taylor C. Wallace and M. Monica Giusti, pp.307-316.

The same study shows that anthocyanins are very stable. Their efficacy for wound healing is documented in a patent.

          Pharmaceutical composition for wound healing containing anthocyanin WO 2008126980. Oct 2008

The antiviral and antimalarial properties of Inula viscosa are well known in the Middle East. The plant is rich in dicaffeoylquinic acid.

          M. Akkawi. Abbasi, S. Jaber, Q. Aburemeleh, A. Naseredin and Pierre Lutgen. Investigation of Traditional Palestinian Medicinal Plant Inula viscosa as Potential Antimalarial Agent British Journal of Pharmacology and Toxicology 2014

          Saleh Abu Lafi, Mutaz Akkawi, Suhair Jaber, Qassem Abu-Remeleh, Mutaz Qutob and Pierre Lutgen. Pure isolates and preparative HPLC fractions or crude extract of Inula viscosa: Effect on β-hematin inhibition in vitro, submitted in August 2017 to the Malariaworld Journal for publication

Inula viscosa was already known in the Bible, in the book of proverbs: “Wounds and browses should be treated with Ra (Inula)”. In the Palestinian village Abud locals use the powder of Inula viscosa leaves or a water extract as a topical treatment for open and bleeding wounds, and it is claimed that it has an efficacy similar to that of iodine. Other plants are known for their wound healing properties, like neem, but the constituents responsible for this property have not been identified.

          BR Wagle, DK Chetri, Evaluation of wound healing properties of Neem (Azadirachta indica) in dogs. Intern J Herbal Medicine, 2017, 5, 05-07

          O Emeka, O Emamoke, O Julius The wound healing effects of aqueous leave extracts of Azadirachta indica on Wistar rats. J Nat Sc Res. 2013, 3, 181-184

Sweet potatoes (Ipomea batatas) and mate tea (Ilex paraguariensis) are rich in anthocyanins and caffeoylquinic acid and are known to protect against fungal diseases and ulcers.

          V Panda, M Sonkamble. Phytochemical constituents and pharmaceutical activities of Ipomea batatas. J Res Phytochem Pharmacol, 2012, 2, 25-34

In the case of Moringa, predominantly 5-o-caffeoylquinic acid and 3-o-caffeoylquinic acid have been detected in the leaves.

           Amaglo N. K., Bennett R. N., Lo Curto R. B., Rosa E. A. S., Lo Turco V., Giuffrid A., Lo Curto A., Crea F., Timpo G. M. (2010).Profiling selected phytochemicals and nutrients in different tissues of the multipurpose tree Moringa oleifera L., grown in Ghana. Food Chem. 122.

           Bennett RN, Mellon FA, Foidl N, Profiling glucosinates and phenolics in vegetative and reproductive tissues of Moringa oleifera. 2003, J Agric Food Chem. 4:51, 3546-53

          VI Hukkeri, CV Nagathan, RV Karadi, Antipyretic and wound healing activities of Moringa oleifera in Rats. Indian J Pharmaceut Sc, 2006, 68. 124-126

Lantana camara is known for its antiulcercic properties. It is rich in anthocyanidins.

          R Sathish, K Natarajan, Antiulcerogenic activity of Lantana camara leaves on gastric ulcers. J Ethnopharmacol 2011 34, 195-7.

          MS Sheeja, A Bopaia, Isolation and Analysis of various anthocyanins from the corolla of Lantana. Int J Pharmac Biolog Archives, 2014, 5, 158-162

The creams of “Mother Nature” in Burundi combining extracts of Artemisia, Moringa and Neem are highly efficient against Buruli ulcer (Jerôme Munyangi, personal communication)

All these molecules are highly water soluble and this explains that aqueous infusions or decoctions are more efficient in wound healing than extracts obtained with organic solvents. And it is likely that many of the therapeutic effects of aqueous decoctions from Artemisia plants are due to these compounds. They contribute to the bitterness of beverages and several people report that the Artemisia annua tea from plantations in Luxembourg is more bitter. Wound healing appears to be a key property of plants of the Asteraceae family.

          Ipek Suntar,The Medicinal Value of Asteraceae Family Plants in Terms of Wound Healing Activity, FABAD J. Pharm. Sci., 39, 21-31, 2014

In India, Artemisia nilagirica (vulgaris) is used against ulcers, leprosy, burns, cuts

          Begum D Nath SC, Ethnobotanical review of medicinal plants used for skin diseases and related problems in northeastern India. India J Herbs Spices Med 2000, 7, 55-93

          AH Merai, PJ Juvatkar. Oxidative damage, Ulcer and leaves of Artemisia vulgaris. Book, Pharmaceutical India Publications Ltd 2012.

The wound healing effect of Artemisia annua was known more than 2000 years ago « The Chinese materia medica literature underlined the use of qinghao (Artemisia annua) for wound healing during the first millenium. It is the sole application recommended in 168 BCE ».

         T.Aftab, JS Ferreira et al. (eds), Artemisia annua – Pharmacology and Biotechnology, Springer Verlag Berlin, Heidelberg, 2014.